Pyrrolidone-5,5-diphosphonic acids

ABSTRACT

Pyrrolidone-5,5-diphosphonic acids having the formula ##STR1## wherein R is a member selected from the group consisting of hydrogen and alkyl having from 1 to 6 carbon atoms; as well as their water-soluble salts. The pyrrolidone-5,5-diphosphonic acids are excellent sequestering agents especially for alkaline earth metal ions. They are stabilizers for percompounds and are useful in the delaying of the setting times for gypsum. In addition, the compounds are useful as cosmetic preparations such as toothpastes and mouthwashes where they prevent formation of tartar and plaque and are useful in therapy in the treatment of diseases related to the abnormal deposition or dissolution of difficultly soluble calcium salts in the animal body.

This is a division of Ser. No. 498,997, filed Aug. 20, 1974, now U.S.Pat. No. 3,960,888.

OBJECTS OF THE INVENTION

An object of the present invention is the obtaining of apyrrolidone-5,5-diphosphonic acid derivative selected from the groupconsisting of (1) compounds of the formula ##STR2## wherein R is amember selected from the group consisting of hydrogen and alkyl havingfrom 1 to 6 carbon atoms, and (2) water-soluble salts thereof.

Another object of the present invention is the development of a processfor the production of the above pyrrolidone-5,5-diphosphonic acids ortheir water-soluble salts.

Another object of the present invention is the development of a processfor the delaying or inhibiting of the precipitation of alkaline earthmetal ions from solution by the use of stoichiometric tosubstoichiometric amounts of the above pyrrolidone-5,5-diphosphonicacids or their water-soluble salts.

A further object of the present invention is the development of a methodfor delaying the setting time for gypsum which comprises adding to themixture of plaster materials and water a small amount of the abovepyrrolidone-5,5-diphosphonic acids or their water-soluble salts.

A yet further object of the present invention is the development of amethod for the treatment of diseases related to the abnormal depositionor dissolution of difficultly soluble calcium salts which comprisesadministering a safe but effective amount of at least one of the abovepyrrolidone-5,5-diphosphonic acids or their water-soluble salts to thewarm-blooded animal.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

DESCRIPTION OF THE INVENTION

The above objects have been achieved by the development of newpyrrolidone-5,5-diphosphonic acid derivatives selected from the groupconsisting of (1) compounds of the Formula I ##STR3## wherein R is amember selected from the group consisting of hydrogen and alkyl havingfrom 1 to 6 carbon atoms, preferably alkyl having 1 to 4 carbon atoms,and (2 ) water-soluble salts thereof; as well as a process for themanufacture of the new compounds and their applications.

The above objects have further been achieved by a method for thetreatment of diseases related to the abnormal deposition or dissolutionof difficulty soluble calcium salts in the warm-blooded animal whichconsists of administering to said warm-blooded animal from 0.05 to 500mg. per kg. of the animal body weight of at least one pharmacologicallyacceptable pyrrolidone-5,5-diphosphonic acid derivative of formula (I)above.

The production of the new pyrrolidone-5,5-diphosphonic acids or theirwater-soluble salts can occur by the reaction of a suitable derivativeof succinic acid with a phosphorus trihalide or phosphorous acid and aphosphorus trihalide and subsequent alkaline hydrolysis of the reactionproduct. In general, the reactions are conducted at temperatures between50° C. and 120° C. The suitable derivatives of succinic acid aresuccinic acid dinitrile and succinic acid diamide. In addition, succinicacid diamides may be employed in which one hydrogen atom in each amidogroup was replaced by an alkyl having from 1 to 6 carbon atoms.

The reaction can be carried out, for example, in that theabove-mentioned succinic acid derivatives are melted with phosphorousacid, and then PCl₃ is slowly added while stirring. The reaction productformed is subsequently subjected to alkaline hydrolysis. This can bedone by boiling with aqueous solutions of strong bases, particularlywith sodium hydroxide or potassium hydroxide solutions.

The above process can also be conducted by starting from succinic aciddinitrile dissolved in an inert solvent such as dioxane or chlorinatedhydrocarbons, and subsequently mixed with phosphorus trihalide. Thenphosphorous acid, preferably dissolved in an inert solvent, is added andthe reaction product is hydrolyzed as above. In the last mentionedmethod, the phosphorous acid can also be omitted, if desired, and acorrespondingly larger amount of phosphorus trihalide employed.

More particularly, the above process for the production of the newpyrrolidone-5,5-diphosphonic acid derivatives of Formula I consistsessentially of the steps of reacting a derivative of succinic acid ofthe formula

    X-- CH.sub.2 -- CH.sub.2 -- X

wherein X is a member selected from the group consisting of --CH,--CONH₂ and --CONHR', where R' is alkyl having 1 to 6 carbon atoms, withat least the stoichiometric amount of a phosphorus reactant selectedfrom the group consisting of a phosphorus trihalide and a mixture of aphosphorus trihalide and phosphorous acid, subjecting the resultingreaction product to an alkaline hydrolysis by the action of an aqueousstrong mineral base, and recovering said pyrrolidone-5,5-diphosphonicacid derivative.

The new pyrrolidone-5,5-diphosphonic acid derivatives of Formula I canalso be produced by reacting a succinic acid monoamide or succinimide inthe above described manner with phosphorus trihalides or phosphorousacid and phosphorus trihalides, and the reaction product is subsequentlyhydrolyzed. In this case, it is not necessary to use an alkalinehydrolysis. The hydrolysis can be effected by adding water withsimultaneous heating.

More particularly the above process for the production of the newpyrrolidone-5,5-diphosphonic acid derivatives of Formula I consistsessentially of the steps of reacting a derivative of succinic acidselected from the group consisting of a compound of the formula ##STR4##and a compound of the formula ##STR5## wherein R is a member selectedfrom the group consisting of hydrogen and alkyl having 1 to 6 carbonatoms, with at least the stoichiometric amount of a phosphorus reactantselected from the group consisting of a phosphorus trihalide and amixture of a phosphorus trihalide and phosphorous acid, subjecting theresulting reaction product to an aqueous hydrolysis at an elevatedtemperature, and recovering said pyrrolidone-5,5-diphosphonic acidderivative.

In the above reactions the phosphorus trihalides which can be used areparticularly phosphorus trichloride and phosphorus tribromide. Thelatter was found to be particularly suitable, if the nitriles areemployed as the starting material.

The molar quantitative ratio of the succinic acid derivatives to thephosphorus reactant is 1:2 to 1:6. If succinic acid dinitrile orsuccinic acid diamides are used, a ratio of 1:4 is preferably utilized.

As far as the pyrrolidone-5,5-diphosphonic acids are obtained after analkaline hydrolysis, they are obtained in the form of the correspondingalkali metal salts. They can be converted, if desired, according toknown methods into the corresponding free acids, for example, by meansof cation-exchangers. For the uses described below, however, the newpyrrolidone-5,5-diphosphonic acid derivatives can be also used in theform of their water-soluble salts, particularly the alkali metal salts,such as the potassium and sodium salts, and ammonium salts. Insofar asthe pyrrolidone-5,5-diphosphonic acid derivatives are obtained directlyin the form of the acids, they can be easily converted into thewater-soluble salts, for example, by partial or complete neutralizationwith corresponding bases.

The salts correspond to the following Formula Ia ##STR6## where Xdenotes hydrogen, NH₄ or a metal cation, such as an alkali metal, butwhere at most three hydrogen atoms are present, R= hydrogen or alkylwith 1 to 6, preferably 1 to 4 carbon atoms.

Finally it was found that the pyrrolidone-5,5-diphosphonic acidderivatives of the Formula I can also be produced by alkalinehydrolyzation of the phosphonic acids of the Formula II ##STR7## whereinR is hydrogen or alkyl having 1 to 6 carbon atoms. By following thismethod the new pyrrolidone-5,5-diphosphonic acid derivatives of FormulaI are obtained in particularly good yields. The salts obtained can thenbe converted, if desired, in known manner into the corresponding acids,for example, by means of cation-exchangers.

The production of the compounds of Formula II can be effected byreacting dicarboxylic acid derivatives of the formula

    X-- (CH.sub.2).sub.2 -- X

where X= CN, CONH₂ or CONHR (R= alkyl radical with 1 to 6 carbon atoms),with phosphorus trihalides and subsequent hydrolyzation of the reactionproduct, as described in our copending Patent Application Ser. No.498,996, filed concurrently herewith, entitled "Cyclic AminophosphonicAcids", now U.S. Pat. No. 3,925,456.

It was analytically determined that the products from all theabove-described production methods correspond to the cyclic Formula Iand that possible products of the open-chained structure of Formula III##STR8## where R denotes hydrogen or alkyl with 1 to 6 carbon atoms,appear only in insignificant amounts.

The new pyrrolidone-5,5-diphosphonic acid derivatives are excellentsequestering agents for polyvalent metal ions, particularly di- andtri-valent metal ions. They are particularly suitable as sequesteringagents for alkaline earth metal ions, so that they can be used for manytechnical applications, such as detergents and cleansers, as well as inwater treatment. They can be employed in stoichiometric andsubstoichiometric amounts as sequestering agents for alkaline earthmetal ions. They also have a stabilizing effect on percompounds.

They are also suitable as additives to delay the setting of gypsum andas ceramic slip liquefiers. For delaying the setting of gypsum, thepotassium, sodium or ammonium salts, in addition to the acids, can alsobe used. The corresponding lithium salts as well as zinc and magnesiumsalts are likewise suitable.

Furthermore, they can be used in mouth washes and tooth pastes in orderto avoid the formation of tartar or plaque. The suitability of thecyclic aminophosphonic acids to be used according to the invention fortartar treatment and prophylaxis, results from their capacity ofinhibiting the formation of crystals in the precipitation of calciumapatite already in small amounts. Calcium apatite, which is precipitatedin the presence of the pyrrolidone-5,5-diphosphonic derivatives,according to the invention, is X-ray amorphous, in contrast tocrystalline apatite, which is usually formed without this addition.

The new pyrrolidone-5,5-diphosphonic acids and their water-solublealkali metal and ammonium salts are suitable as pharmacological activesubstances in pharmaceutical products. They have therapeutic and/orprophylactic effects in the treatment of a number of diseases, which arerelated to the abnormal deposition of dissolution of difficultly solublecalcium salts in the animal body. These diseases can be divided into twocategories:

(1) Abnormal depositions of difficultly soluble calcium salts, mostlycalcium phosphate, cause bone malformations, pathological hardening oftissues and secretions in organs.

(2) The abnormal dissolution of hard tissues causes losses of hard bonesubstance, which cannot be replaced or only by incompletely crystallizedtissue. This dissolution is frequently accompanied by pathologicallyhigh calcium and phosphate concentrations in the plasma.

These diseases include: osteoporosis, osteodystrophy, Paget's disease,myositis ossificans, Bechterew's disease, cholelithiasis,nephrolithiasis, urinary calculus, hardening of the arteries(sclerosis), arthritis, bursitis, neuritis, tetany.

In addition to the free pyrrolidone-5,5-diphosphonic acids, theirpharmacologically harmless salts, such as the alkali metal salts, forexample, sodium or potassium or the ammonium salts or the substitutedammonium salts, such as the lower alkanol ammonium salts like the mono-,di-, or tri-ethanol ammonium salts can be used, for use inpharmaceutical preparations in the treatment of these diseases or fortheir prophylaxis. Both the partial salts, in which only a part of theacid protons are replaced by other cations, and full salts can be used,but partial salts, which react substantially neutral in aqueous solution(pH 5 to 9) are preferred. Mixtures of the above-mentioned salts canlikewise be used.

The dosage range of the pyrrolidone-5,5-diphosphonic acid derivativescan be from 0.05 to 500 mg per kg of the animal body weight. Thepreferred dose is 1 to 20 mg per kg of body weight, and can beadministered up to 4 times daily. The higher doses are necessary fororal application, due to the limited resorption. Doses under 0.05 per kgof body weight have little effect on the pathological calcification ordissolution of bone substance. Doses above 500 mg/kg of body weight mayhave toxic side effects in the long run. Thepyrrolidone-5,5-diphosphonic acid derivatives can be administeredorally, subcutaneously or intraperitoneally in the form of tablets,pills, capsules or as injectable solutions. For animals thepyrrolidone-5,5-diphosphonic acid derivatives can also be used as partof the feed or of feed additives.

The following examples are illustrative of the practice of the inventionwithout being limitative thereof in any respect.

EXAMPLE 1 Pyrrolidone-5,5-diphosphonic acid ##STR9##

(a) 24.4 gm of2-hydroxy-2-oxo-3-amino-3-phosphonyl-6-oxo-1-aza-2-phosphacyclohexane(see Formula II) (0.12 mol) were heated with 400 ml of 2N sodiumhydroxide solution to the boiling point for a period of time until nofurther ammonia escapes with the steam. The solution was thenconcentrated to 100 ml and mixed with 300 ml of ethanol. Theprecipitation of the sodium salt of the pyrrolidone-5,5-diphosphonicacid was completed with acetone and ethyl acetate. The oily substancewas separated, dissolved again in H₂ O and passed through a cationexchanger in the hydrogen cycle. The solution obtained was concentratedto 100 ml, and the pyrrolidone-5,5-diphosphonic acid was precipitatedwith 300 ml of ethanol, 200 ml of acetone, and 200 ml of ethyl acetate.Yield 14.3 gm= 63% of the theory.

(b) 58.5 gm of succinic acid monoamide (0.5 mol) and 41 gm of H₃ PO₃(0.5 mol) were melted at 70° C. and mixed slowly with stirring with 43.8ml of PCl₃ (0.5 mol). After 3 hours at 70° C. the product was hydrolyzedwith 200 ml of H₂ O and boiled with activated carbon. The hot solutionwas filtered and the pyrrolidone-5,5-diphosphonic acid was precipitatedfrom the filtrate with 400 ml of ethanol and 400 ml of acetone. Crudeyield 5.0 gm= 3.8% of the theory.

(c) 49.5 gm of succinimide (0.5 mol) and 41 gm of H₃ PO₃ (0.5 mol) wereheated to 70° C. To the homogeneous melt, 43.8 ml of PCl₃ (0.5 mol) wereadded slowly in drops. The reaction product was held for 4 hours at 70°C. and then hydrolyzed with 200 ml of H₂ O as (b) above. Thepyrrolidone-5,5-diphosphonic acid was precipitated from the filtratewith 300 ml of ethanol and 300 ml of acetone. Crude yield 4.6 gm= 3.5%of the theory.

(d) 40 gm of succinic acid dinitrile (0.5 mol) were dissolved in 400 mlof dioxane and 190 ml of PBr₃ were added slowly in drops. After stirringfor another 4 hours at 70° C. the viscous yellow mass was hydrolyzedwith 300 ml of water. After filtration with activated carbon, thedioxane was separated.

The aqueous phase was mixed with 500 ml of 6N NaOH and heated until nofurther ammonia escaped. By adding an ethanol/acetone mixture, thesodium salt of pyrrolidone-5,5-diphosphonic acid was precipitated.

The free pyrrolidone-5,5-diphosphonic acid according to (a) to (c) wasobtained after drying at 50° C. as a monohydrate with a titrimetricallydetermined molecular weight of 265 (calc. 263.1). On drying at 80° C. ina vacuum oven, the anhydrous compound was obtained with a molecularweight of 247 (calc. 245.07).

    ______________________________________                                        Analysis:                                                                     Calculated: 19.60% C 3.70% H  5.71% N                                                                              25.28% P                                 Found:      19.34    3.61     5.66   25.24                                    ______________________________________                                    

In the IR-spectrum the compound showed a strong νCO band at 1,610cm.sup.⁻¹, M.P. 250° C. with decomposition.

EXAMPLE 2 N-methyl-pyrrolidone-5,5-diphosphonic acid ##STR10##

(a) 64.4 gm of1-methyl-2-hydroxy-2-oxo-3-methylamino-3-phosphonyl-6-oxo-1-aza-2-phospha-cyclohexane(0.237 mol) were heated with 800 ml of a 2N KOH solution to the boilingpoint for a period of time until no further methylamine passes over withsteam. After filtration, the potassium salt ofN-methyl-pyrrolidone-5,5-diphosphonic acid was separated from thealkaline solution by precipitation with ethanol and acetone. Thepotassium salt was again dissolved in H₂ O and passed through a cationexchanger in the hydrogen cycle. TheN-methyl-pyrrolidone-5,5-diphosphonic acid was isolated from theconcentrated solution with ethanol and acetone. Yield 16.4 gm (27% ofthe theory).

(b) 28.5 gm of succinic acid monomethylamide (0.216 mol) were meltedwith 35.4 gm of H₃ PO₃ (0.432 mol) at 70° C. and then slowly mixed with37.8 ml of PCl₃ (0.432 mol). After an additional 5 hours at 70° C., theproduct was hydrolyzed with 300 ml of H₂ O. Filtration with activatedcarbon at the boiling point yielded a clear solution from which theN-methyl-pyrrolidone-5,5-diphosphonic acid was precipitated with ethanoland acetone. Crude yield 4.2 gm (7% of the theory).

The N-methyl-pyrrolidone-5,5-diphosphonic acid was obtained after dryingat 50° C. as a monohydrate with a molecular weight of 279 (calc. 277.1).After drying at 80° C. in the vacuum oven, the anhydrous compound wasobtained with a molecular weight of 259 (calc. 259.1).

    ______________________________________                                        Analysis:                                                                     Calculated:  23.18% C 4.28% H  5.41% N                                                                              23.91% P                                Found:       22.90    4.16     5.45   23.12                                   ______________________________________                                    

The compound shows in the IR-spectrum a strong νCO band at 1,650cm.sup.⁻¹, M.P. above 270° C. with decomposition.

EXAMPLE 3 N-ethyl-pyrrolidone-5,5-diphosphonic acid ##STR11##(d)

(a) 88.5 gm of1-ethyl-2-hydroxy-2-oxo-3-ethylamino-3-phosphonyl-6-oxo-1-aza-2-phospha-cyclohexane(0.295 mol) were boiled with 147.5 gm of a 40% NaOH solution (1.475 mol)for a length of time until no further ethylamine escaped. Then theproduct was filtered with activated carbon and the sodium salt ofN-ethyl-pyrrolidone-5,5-diphosphonic acid was precipitated with ethanoland acetone. The oily substance was again dissolved in H₂ O and passedthrough a cation exchanger in the hydrogen cycle, and theN-ethyl-pyrrolidone-5,5-diphosphonic acid was isolated from the extractwith ethanol and acetone. Yield 79 gm (90% of the theory).

(b) 43.0 gm of succinic acid bisethylamide (0.25 mol) were melted with82 gm of H₃ PO₃ (1.0 mol) at 70° C. To the melt, 88 ml of PCl₃ (1.0 mol)were slowly added in drops and the mixture was left standing for 5 hoursat 70° C. Then the mixture was hydrolyzed with 250 ml of H₂ O andfiltered with activated carbon. The filtrate was mixed with 0.5 liter of6N NaOH solution and heated so long until no further ethylamine passedover. The sodium salt of N-ethyl-pyrrolidone-5,5-diphosphonic acid wasprecipitated with ethanol/acetone, dissolved again in H₂ O and passedthrough a cation exchanger in the hydrogen cycle. TheN-ethyl-pyrrolidone-5,5-diphosphonic acid was precipitated from theextract with ethanol and acetone. Yield 16.5 gm (22% of the theory).After drying at 50° C., the substance was obtained as a monohydrate witha molecular weight of 292 (calc. 291.1).

    ______________________________________                                        Analysis:                                                                     Calculated:   24.75% C  5.19% H   21.28% P                                    Found:        24.79     5.06      21.08                                       ______________________________________                                    

After drying in the vacuum oven at 80° C., the anhydrous compound wasobtained with a molecular weight of 276 (calc. 273.1).

In the IR-spectrum the substance shows a strong ν CO band at 1640 cm⁻ ¹,M.P. 250° C.

EXAMPLE 4 N-butyl-pyrrolidone-5,5-diphosphonic acid ##STR12##

40 gm of1-butyl-2-hydroxy-2-oxo-3-butylamino-3-phosphonyl-6-oxo-1-aza-2-phospha-cyclohexane(0.112 mol) were boiled with 400 ml of 2N NaOH solution for a length oftime until no further butylamine escaped. Then the mixture was filteredwith activated carbon and the sodium salt ofN-butyl-pyrrolidone-5,5-diphosphonic acid was isolated withethanol/acetone. The oily substance was dissolved in water and passedthrough a cation exchanger in the hydrogen cycle. TheN-butyl-pyrrolidone-5,5-diphosphonic acid was isolated from theconcentrated extract with ethanol and acetone. Yield 23 gm (58% of thetheory).

After drying at 50° C., the compound was obtained as a monohydrate.

The molecular weight was determined titrimetrically as 321 (calc.319.2).

    ______________________________________                                        Analysis:                                                                     Calculated: 30.10% C 6.00% H 4.39% N                                                                              19.41% P                                  Found:      30.02    5.66    4.27   18.64                                     ______________________________________                                    

After drying at 80° C. in a vacuum oven, the anhydrous compound wasobtained with a molecular weight of 303 (calc. 301.2) the compound showsin the IR-spectrum a strong ν CO band at 1660cm⁻ ¹, M.P. over 240° C.with decomposition.

EXAMPLE 5 PREPARATION OF SALTS

(a) 25.9 gm of N-methyl-pyrrolidone-5,5-diphosphonic acid were dissolvedin 100 ml of water and mixed with 100 ml of a 4N lithium hydroxidesolution. On addition of 300 ml of ethanol, the tetra-lithium salt ofN-methyl-pyrrolidone-5,5-diphosphonic acid was precipitated.

(b) 27.31 gm of N-ethyl-pyrrolidone-5,5-diphosphonic acid were dissolvedin 100 ml of water and mixed with 100 ml of a 2N NH₄ OH solution. Onaddition of 300 ml of ethanol, the di-ammonium salt ofN-ethyl-pyrrolidone-5,5-diphosphonic acid was precipitated.

(c) 24.5 gm of pyrrolidone-5,5-diphosphonic acid (0.1 mol) weredissolved in 100 ml of water. To this solution, a solution of 13.6 gm ofZnCl₂ (0.1 mol) dissolved in 50 ml of water was added. The precipitationof the zinc salt of pyrrolidone-5,5-diphosphonic acid was completed bythe addition of 300 ml of ethanol.

d. The magnesium salt of pyrrolidone-5,5-diphosphonic acid was obtainedby replacing the ZnCl₂ by 9.4 gm of MgCl₂ (0.1 mol) using the sameprocedure as described under (c).

EXAMPLE 6 Sequestration of calcium

In the investigation of the sequestration of calcium, a modifiedHampshire test was employed and worked as follows:

1 gm of the sequestering agent was dissolved in 50 ml of H₂ O, adjustedwith NaOH to a pH of 11. 50 ml of a Ca⁺ ⁺ solution (1470 mg ofCaCl₂.sup.. 2H₂ O/1) were mixed with 100 ml of a sodium carbonatesolution (7.15 gm NaCO₃.sup.. 10H₂ O/1). Then the solution of thesequestering agent was added in drops from a burette until the calciumcarbonate precipitate was redissolved. The values formed have beenreported in Table I. For the sake of simplicity, only the value for thevarious substituents for R according to Formula I are indicated in theleft column of the Table.

                  TABLE I                                                         ______________________________________                                         ##STR13##                                                                    R = H or alkyl having 1 to 6 carbon atoms.                                               Consumption of                                                                Sequestering   mg CaCO.sub.3 Seques-                               Compound   Agent Solution tered per gm of                                     R          (ml)           Compound                                            ______________________________________                                        H          2.9            865                                                 CH.sub.3   2.6            960                                                 C.sub.2 H.sub.5                                                                          2.5            1000                                                C.sub.4 H.sub.9                                                                          2.9            865                                                 ______________________________________                                    

practically identical results were obtained if, instead of the acids,the corresponding sodium, potassium or ammonium salts were employed.

EXAMPLE 7 Threshold Effect

The prevention of the precipitation of poorly soluble calcium compoundsby substoichiometric amounts of a sequestering agent was determined withthe Hampshire test at room temperature. The procedure was as follows:

50 mg of the sequestering agent were dissolved in 10 ml of H₂ O(standardized with NaOH to pH 11) and mixed with 100 ml of a sodiumcarbonate solution (14.3 gm of NaCO₃.sup.. 10H₂ O/1). Then sufficient ofa calcium solution (36.8 gm of CaCl₂.sup.. 2H₂ O/1) was added in dropsfrom a burette until a permanent cloudiness was just formed. Table IIreports the results of these tests. For an explanation of the data inthe left-hand column of the Table, see Example 6.

                  TABLE II                                                        ______________________________________                                                  Consumption            mg CaCO.sub.3                                          of Ca                  Sequestered                                  Substance Solution               per gm of                                    R         (ml)        Mg CaCO.sub.3                                                                            Compound                                     ______________________________________                                        H         2.1         52.5       1050                                         CH.sub.3  2.8         70.0       1400                                         C.sub.2 H.sub.5                                                                         3.3         82.5       1650                                         C.sub.4 H.sub.9                                                                         2.2         55.0       1100                                         ______________________________________                                    

Practically identical results are obtained if, instead of the acids, thecorresponding sodium, potassium or ammonium salts were employed.

EXAMPLE 8 Delay of setting of Gypsum

Gypsum materials in the form of plaster, plaster of Paris, or in mixturewith aggregates, like limestone, sand, perlite or cellulose, setrelatively fast, so that rapid processing must take place. A delay ofthe setting time can be achieved with the addition of theabove-described phosphonic acids, and the processing of the gypsummaterials can thus be considerably facilitated.

In the following tests, each of the various phosphonic acids of theinvention was added to the water before the gypsum was mixed. However,water-soluble salts of the phosphonic acids, particularly the lithium,sodium, potassium and ammonium salts can also be mixed instead with thegypsum or added shortly after the mixing of the gypsum material togetherin the water. Specifically the following setting values were found andreported in Table III, using in each test 20.0 gm of gypsum and 9 ml ofH₂ O. The setting time is the time interval in which the gypsum wasspreadable and easy to handle.

For the explanation of the data in the left column of Table III, seeExample 6.

                  TABLE III                                                       ______________________________________                                        Substance    Amount    Setting Time                                           R            (mg)      (min.)                                                 ______________________________________                                         --          --         15                                                    H            45        160                                                    CH.sub.3     45        140                                                    C.sub.2 H.sub.5                                                                            45        120                                                    C.sub.4 H.sub.9                                                                            45        110                                                    ______________________________________                                    

Comparable results are obtained by using the corresponding magnesium andzinc salts.

EXAMPLE 9 Pharmaceutical Application (a) Calcium phosphate dissolutionin vitro

Essential tests for the effectiveness of the compounds in physiologicalsystems are in vitro tests for the dissolving of freshly precipitatedCaHPO₄ at a pH of 7.4 The "CaHPO₄ test" was carried out as follows:

By combining 25 ml of a phosphate solution (1.38 gm of NaH₂ PO₄.sup.. H₂O/liter, standardized to a pH of 7.4) and 25 ml of a calcium solution(1.47 gm of CaCl₂.sup.. 2H₂ O/liter, standardized to a pH of 7.4), aprecipitate of CaHPO₄ was produced. Thereafter, so much of a solution ofthe sequestering agent (at a concentration of 10 mg/ml) was addeddropwise from a burette that a clear solution was obtained afterstanding for one hour.

The results are compiled in the following Table IV. The explanation ofthe data in the left column is to be found in Example 6.

                  TABLE IV                                                        ______________________________________                                        Dissolution of CaHPO.sub.4 Precipitation                                                Consumption                                                                   Sequestering                                                        Substance Agent Solution                                                                              mg CaHPO.sub.4 dissolved                              R         (ml)          gm Sequestering Agent                                 ______________________________________                                        H         3.8           900                                                   CH.sub.3  3.8           900                                                   C.sub.2 H.sub.5                                                                         4.4           775                                                   C.sub.4 H.sub.9                                                                         4.8           710                                                   ______________________________________                                    

(b) Prevention of hardening of the aorta in rats

The effectiveness of the pyrrolidone-5,5-diphosphonic acids of thepresent invention in preventing abnormal calcium deposits in vivo inrats can be demonstrated as follows.

This test was based on the observation that high doses of vitamin D₃cause a considerable hardening of the aorta in rats. 30 Female ratsweighing 150 to 200 gm each were divided into three groups of tenanimals each. They received during the test period a normal diet and tapwater ad libitum. One group of ten animals (control) received no furthertreatment. Another group of the animals received from the 3rd to the 7thday, 75,000 units of vitamin D₃ daily through a stomach sound. The thirdgroup likewise received from the 3rd to the 7th day, 75,000 units ofvitamin D₃ daily through a stomach sound and, in addition, likewiseorally, 10 mg per kg of one of the pyrrolidone-5,5-diphosphonic acidsfrom the 1st to the 10th day. After ten days the animals were sacrificedand their aortas prepared and dried for 12 hours at 105° C. Afterdetermination of the dry weight, the aortas were ashed; the residue wasdissolved, and the calcium was determined by flame photometry. Thetreatment with all the pyrrolidone-5,5-diphosphonic acids mentionedabove reduced the vitamin D₃ induced hardening of the aortas of ratsconsiderably.

(c) Apatite crystallization delay test in vitro

The effectiveness of the compounds according to the invention for theabove-mentioned purposes was also demonstrated in vitro by acrystallization delay test.

Supersaturated solutions of Ca⁺ ⁺ and HPO₄ ⁻ ⁻ ions are relativelystable, but crystallize after the addition of an apatite nucleiaccording to the reaction

    5 Ca.sup.+.sup.+ + 3 HPO.sub.4 .sup.-.sup.- + H.sub.2 O→ Ca.sub.5 (PO.sub.4).sub.3 OH+ 4 H.sup.+

with the release of protons. The reaction can, therefore, be readilyobserved by titration with a base at a constant pH.

400 ml of 0.0008 molar KH₂ PO₄ solution were mixed with 45 ml of a 0.012molar CaCl₂ solution, and the clear solution was standardized with KOHto a pH of 7.4, after being brought to a temperature of 35° C. After 30minutes during which time the pH did not change, a suspension of 100 mghydroxyl apatite in 50 ml of H₂ O was added. The crystallization set inimmediately and was followed by "pH-Stat" titration with 0.05 N KOH.

If a small amount of one of the pyrrolidone-5,5-diphosphonic acids ofthe invention was added to the solution before the apatite was added,the crystallization was greatly delayed.

The inhibition of the crystallization with 2 mg ofpyrrolidone-5,5-diphosphonic acid is over 90% in a period of 8 hours,with 2 mg N-methyl-pyrrolidone-5,5-diphosphonic acid it is over 80% in aperiod of 8 hours.

EXAMPLE 10 Pharmaceutical Compositions

For the production of a pharmaceutical preparation in the form of acapsule, the known methods of preparation are followed to preparecapsules having a content per capsule as follows:

    ______________________________________                                        Pyrrolidone-5,5-diphosphonic                                                  acid                     100 mg                                               Starch                    20 mg                                               Sodium laurylsulfate      1 mg                                                ______________________________________                                    

For the preparation of a tablet, the following recipe was utilized pertablet:

    ______________________________________                                        N-methyl-pyrrolidone-5,5-                                                     diphosphonic acid        50 mg                                                Lactose                 100 mg                                                Starch                   35 mg                                                Magnesium stearate       2 mg                                                 ______________________________________                                    

EXAMPLE 11 Cosmetic Preparations

The following recipes are suitable as a basic formula for tooth pastes:

    ______________________________________                                                              Parts by Weight                                         (a) Glycerin                60.0                                                  Water                   13.5                                                  Sodium carboxymethyl-cellulose                                                                        0.6                                                   Silicic acid xerogel    20.0                                                  Sodium laurylsulfate    2.0                                                   Essential oils          1.0                                                   Sweetening agent        0.4                                                   Pyrrolidone-5,5-diphosphonic acid                                                                     2.5                                               (b) Glycerin                30.0                                                  Water                   18.5                                                  Sodium carboxymethyl-cellulose                                                                        1.0                                                   Aluminum hydroxide      44.0                                                  Sodium laurylsulfate    1.0                                                   Pyrogenic silica        1.5                                                   Essential oils          1.5                                                   Sweetening agent        0.5                                                   Pyrrolidone-5,5-diphosphonic acid                                                                     2.0                                               ______________________________________                                    

Suitable as a basic formulation for mouthwashes is the following recipe:

    ______________________________________                                                            Parts by Weight                                           Ethyl alcohol         19.5                                                    Glycerin              7.5                                                     Water                 70.0                                                    Essential oils        0.2                                                     Sodium laurylsulfate  0.1                                                     Antiseptic (chlorothymol)                                                                           0.1                                                     Sweetening agent      0.1                                                     Pyrrolidone-5,5-diphosphonic acid                                                                   2.5                                                     ______________________________________                                    

Instead of pyrrolidone-5,5-diphosphonic acid, the corresponding amountsof N-alkylpyrrolidone-5,5-diphosphonic acids (alkyl radical with 1 to 6carbon atoms) can also be employed.

By regular use of the mouthwashes and/or toothpastes containing theabove-mentioned pyrrolidone-5,5-diphosphonic acids, the formation oftartar could be considerably reduced. The formation of hard compactplaque on the teeth was to a great extent prevented.

The preceding specific embodiments are illustrative of the practice ofthe invention. It is to be understood, however, that other expedientsknown to those skilled in the art are discussed herein may be employedwithout departing from the spirit of the invention or the scope of theappended claims.

We claim:
 1. A method for alleviating conditions caused by the abnormaldeposition or dissolution of difficultly soluble calcium salts in thebody of warm-blooded animals having said condition, which consists inadministering to said warm-blooded animals a safe but effective amountfor said treatment of from 0.05 to 500 mg per kg. of body weight of atleast one pharmacologically acceptable pyrrolidone-5,5-diphosphonic acidcompound selected from the group consisting of (A) a compound of theformula: ##STR14## wherein R represents hydrogen and alkyl having 1 to 6carbon atoms, and (B) non-toxic, pharmaceutically acceptable saltsthereof.
 2. The method of claim 1 wherein R is hydrogen.
 3. The methodof claim 1 wherein R is methyl.
 4. The method of claim 1 wherein R isethyl.
 5. The method of claim 1 wherein R is butyl.
 6. A methodaccording to claim 1 wherein the compound is administered orally.
 7. Amethod according to claim 1 wherein the compound is administered as atablet.